Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia

Abstract

Pontocerebellar Hypoplasia (PCH) is group of very rare, inherited progressive neurodegenerative disorders with prenatal onset. Up to now seven different subtypes have been reported (PCH1-7). The incidence of each subtype is unknown. All subtypes share common characteristics, including hypoplasia/atrophy of cerebellum and pons, progressive microcephaly, and variable cerebral involvement. Patients have severe cognitive and motor handicaps and seizures are often reported. Treatment is only symptomatic and prognosis is poor, as most patients die during infancy or childhood. The genetic basis of different subtypes has been elucidated, which makes prenatal testing possible in families with mutations. Mutations in three tRNA splicing endonuclease subunit genes were found to be responsible for PCH2, PCH4 and PCH5. Mutations in the nuclear encoded mitochondrial arginyl- tRNA synthetase gene underlie PCH6. The tRNA splicing endonuclease, the mitochondrial arginyl- tRNA synthetase and the vaccinia related kinase1 are mutated in the minority of PCH1 cases. These genes are involved in essential processes in protein synthesis in general and tRNA processing in particular. In this review we describe the neuroradiological, neuropathological, clinical and genetic features of the different PCH subtypes and we report on in vitro and in vivo studies on the tRNA splicing endonuclease and mitochondrial arginyl-tRNA synthetase and discuss their relation to pontocerebellar hypoplasia.

Figure 1

MRI sections of cases with PCH type 1, type 2 and type 4. The images of the PCH1 case were kindly provided by Professor Darin, The Queen Silvia. Children's Hospital, Gothenburg University, Sweden. 1A-C: Images of a 2 wk old neonate with PCH1. 1A: Mid-sagittal section (T1) shows vermal hypoplasia and marked cerebellar hypoplasia. 1B: Lateral sagittal section (T1) shows severe hypoplasia of the cerebellar hemispheres. 1C: Coronal section (T2) shows flattened cerebellar hemispheres which also display some atrophy. The vermis is relatively spared. 1D-E: Images of a 2 months old baby with PCH2. 1D: Mid-sagittal section (T1IR) shows a flat ventral pons and vermal hypoplasia. 1E: Lateral sagittal section (T1IR) shows severely hypoplastic cerebellar hemispheres (arrow) leaving most of the posterior fossa empty. 1F: Coronal section (T2) of a 9 months old infant with PCH2 shows flat cerebellar hemispheres and mild vermal hypoplasia (dragonfly configuration). Cerebral cortical atrophy is also present. 1G-I: Images of a 31+5 weeks neonate with PCH4. 1G: Mid-sagittal section (T2) shows severe vermal hypoplasia and ventral pontine flattening. 1H: Lateral sagittal section (T2) shows severe hypoplasia of the cerebellar hemispheres. Above the tentorium there is an increased distance between the cortical surface and the skull visible, which is probably due to diminished brain growth in utero. 1I: Coronal section (T1) shows extremely small and flattened cerebellar hemispheres and severe vermal hypoplasia. Immaturity of cerebral cortex and enlarged ventricles are also visible.

Figure 2

Different RNA processing events in mammals. 2A: Eukaryotic splicing pathway of tRNA splicing in mammals. The TSEN complex is involved in the maturation of premature tRNAs and excises the tRNA into two halves; one 5'tRNA half with a 2'-3' cyclic phosphate at one exon-end and a 3'tRNA half with a 5'OH-group at the other exon-end. The final processing of tRNA maturation involves either direct ligation of the two tRNA halves by ligation through the Archaea-like pathway (by HSPC117, depicted) or indirect ligation through the yeast-like pathway (not depicted) [104]. Adapted from Calvin et al. [105]. 2B: tRNA aminoacylation in mammals. RARS2 can bind to its cognate amino acid in an ATP dependent matter. This complex of ATP, RARS2 and arginine binds to the mt-tRNA-Arg and arginine will be transferred to its tRNA. Adapted from Antonellis et al. [83]. 2C: Selenocysteine synthesis. Serine (Ser) is aminoacylated to tRNA-Sec by a seryl-tRNA synthetase (SARS). This Ser-tRNA-Sec complex is then converted by a kinase to a Sep-tRNA-Sec complex. In the presence of the cofactor pyridoxal phosphate (PLP) and the selenium donor selenophosphate (Se-donor) the SEPSECS enzyme converts the Sep-tRNA-Sec to Sec-tRNA-Sec. Adapted from Allmang et al. [87].